A 52-Year-Old Man with Ecchymotic Leg Ulcers

Journal of the Louisiana State Medical Society Clinical Case of the Month

A 52-Year-Old Man With Ecchymotic Leg Ulcers

Seema Walvekar, MD; Jessica L. Johnson, PharmD, BCPS; Emily Kauffman, DO; Rachna Jetly, MD; Bennett P. deBoisblanc, MD, FCP, FACCP, FCCM

CASE PRESENTATION He was transfused with packed red blood cells and fresh frozen plasma. Therapy for presumed warfarin-induced A 52-year-old man presented to the emergency depart- skin necrosis (WISN), i.e. heparin or recombinant activated ment with a one-day history of pain and bluish discoloration protein C infusion, was withheld due to the elevated INR, of the tips of the great toes of both his feet that rapidly pro- thrombocytopenia, and a low hemoglobin level. gressed to worsening pain, swelling, and discoloration of Skin punch biopsy of the purpura over his legs showed both feet and legs. His past medical history was significant separation of the stratum corneum, focal necrosis of acrosyr- for many years of heavy alcohol use and an episode of un- inx, and thrombosis of blood vessels throughout the dermis provoked venous thromboembolism two months prior to and subcutaneous tissue (Figure 2). There was no evidence presentation. At that time, he was found to be heterozygous of vasculitis. He ultimately developed limb gangrene, re- for Factor V Leiden mutation. After initial anticoagulation quiring bilateral above knee amputations. with fondaparinux, he was started on warfarin 7.5 mg daily. A removable inferior vena cava filter was placed for unclear DISCUSSION indications. In the emergency department, his review of systems was remarkable for a one-day history of melena Skin necrosis is a rare complication of anticoagula- with hematemesis. On subsequent questioning, he admit- tion with warfarin that results from extensive thrombotic ted to only sporadic compliance with his warfarin therapy and laboratory monitoring. On physical examination, the patient was noted to have hemorrhagic bullae of the skin of the anterior pretibial surfaces of both legs (Figure 1). His laboratory data was significant for a hemoglobin of 3 g/dl (13.5-17.5 gm/ dl), white blood cell count 28,000/ mm3 (normal 4.5,000-11,000/mm3), platelet count 54,000/mm3 (normal 130,000-400,000/mm3, International Normalized Ratio (INR) > 9.5 (normal 0.9-1.1) quantitative D-dimer >5000 ng/mL(normal <200 ng/dl), and fibrinogen 311 mg/dL (normal 200-600 mg/dl). No gastrointestinal source of bleeding was identified on esophagogastroduodenoscopy. Ultrasound demonstrated bilateral popliteal thrombosis. Within hours, hemorrhagic bullae formed over both pretibial areas, and purpura began Figure 1: Photograph of our patient’s right leg demonstrating hemorrhagic bullae to appear on his upper extremities. characteristic of warfarin-induced skin necrosis.

232 J La State Med Soc VOL 165 May/June 2013 Table: Half-life of Vitamin K-depedent clotting factors1,2 clotting factors and thus, to prevent WISN in patients with protein C deficiency until this procoagulant factors are Protein C 8 hours cleared, typically by day five of therapy.3 Factor IX 24 hours WISN has an estimated incidence of 0.01-0.1% in the general population of patients receiving oral Vitamin K Factor X 48 hours antagonists.1 However, as many as one-third of these cases Factor II 2-5 days occur in patients who are heterozygous for protein C or S deficiency.4 WISN has not only been associated with ac- Factor IV 1-6 hours quired and hereditary deficiencies of proteins C and S, but Protein S 42 hours also with activated protein C (APC) resistance secondary to Factor V Leiden mutation.4-8 occlusion of small vessels, resulting in large areas of der- APC downregulates the production of thrombin by mal necrosis requiring debridement or limb amputation. enzymatically deactivating clotting factors Va and VIIIa. Clinical mimics of WISN include: necrotizing fasciitis, pur- APC resistance is a common risk factor for thrombosis, and pura fulminans, calciphylaxis, cryoglobinemia, cholesterol between 20% and 60% of thrombophilic patients suffer from embolization, heparin-induced skin necrosis, and lupus some form of APC resistance.9,10 The most common point anticoagulant-associated skin necrosis. These conditions mutation leading to APC resistance among Caucasians is must be ruled out to consider a diagnosis of WISN. at the R506Q site of Factor Va (FVa), known as the Factor The most plausible hypothesis explaining WISN is that V Leiden mutation. initiation of warfarin treatment causes a transient imbalance Procoagulant FVa is deactivated by APC with an initial of pro- and anti-coagulant factors that favors thrombosis. cleavage of the FVa peptide at the Arg506 position, followed Within the first 24 hours of an initial dose, warfarin reduces by a second cleavage at Arg306. The Factor V Leiden R506Q the anticoagulant activity of protein C by almost 50%. How- point mutation, a substitution of arginine with glutamine, ever, the activity of Vitamin K-dependent procoagulant prevents cleavage at that position by APC. Although the factors is inhibited by warfarin at a much slower rate due mutant FVa can be inactivated by cleavage at Arg306, this to the longer half-lives of these factors (Table). The slower cleavage is tenfold slower without prior cleavage at Arg506. clearance of the procoagulant factors leads to transient hy- Once cleaved at Arg506 by APC, deactivated FV functions as percoagulability and the potential for thrombosis during a cofactor in the APC-mediated degradation of Factor VIIIa. this early phase of warfarin therapy.1,2 This mechanism is Individuals with Factor V Leiden mutation therefore have more pronounced when higher doses of warfarin are used decreased deactivation of both FVa and FVIIIa and increased or when a patient has a genetic or acquired protein C de- risk of thrombosis.9-11 ficiency. Heparin bridging is used to inhibit procoagulant Individuals who are heterozygous for the Factor V Figure 2: Photomicrograph of a skin punch biopsy demonstrating thrombosis of blood vessels (arrows) throughout the dermis and subcutaneous tissue.

J La State Med Soc VOL 165 May/June 2013 233 Journal of the Louisiana State Medical Society

Leiden mutation carry a risk of venous thrombosis five to 6. Teepe RG, Broekmans AW, Vermeer BJ, Nienhuis AM, Loeliger seven times higher than that of the general population; ho- EA. Recurrent coumarin-induced skin necrosis in a patient mozygous subjects have a risk 80 times higher. The incidence with an acquired functional protein C deficiency. Arch Dermatol of Factor V Leiden mutation among the general Caucasian 1986;122(12):1408. 7. Sallah S, Abdallah JM, Gagnon GA. Recurrent warfarin-induced population is 0-8%, but up to 60% of patients with venous skin necrosis in kindreds with protein S deficiency. Haemostasis thromboembolism may test positive for Factor V Leiden 1998;28(1):25. 9-11 mutation. 8. Makris M, Bardhan G, Preston FE. Warfarin induced skin necrosis Approximately 95% of patients who are heterozygous associated with activated protein C resistance. Thromb Haemost for Factor V Leiden mutation at the chromosome R506Q 1996;75(3):523. demonstrate APC resistance.8 Additional sources of APC 9. Nicolaes GAF, Dahlbäck B. Congenital and Acquired Activated resistance include other point mutations of Factor V, spon- Protein C Resistance. Seminars in Vascular Medicine 2003;03(1): taneous generation of auto-antibodies targeting Factor V, 033-046. 10. Dahlbäck B. The discovery of activated protein C resistance. J and dysfunction or deficiency of APC cofactors, including Thromb Haemost 2003 Jan;1(1):3-9. protein S. 11. Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM. Warfarin- induced skin necrosis. J Am Acad Dermatol 2009;60(2):325-332. CASE SUMMARY

Our patient was predisposed to developing WISN. Drs. Walvekar and Kauffman are with the Department of Internal He was heterozygous for Factor V Leiden mutation at the Medicine at the Louisiana State University Health Sciences Center R506Q position, increasing his risk of thrombosis. Patients in New Orleans. Dr. Kauffman is a Resident there. Dr. Johnson is a with Factor V Leiden mutation are at increased risk of Clinical Assistant Professor at Xavier University of Louisiana College WISN, particularly when warfarin is initiated in high doses of Pharmacy and is affiliated with Interim Louisiana Hospital, Medical or without heparin bridging. Our patient admitted to inter- Intensive Care Unit at LSUHSC-New Orleans. Dr. Jetly is with the mittent compliance to prescribed therapy and monitoring. Department of Pathology at LSUHSC-New Orleans. Dr. deBoisblanc is a Professor of Medicine and Pathology and is affiliated with the He stopped and started high-dose warfarin several times Pulmonary section of Critical Care at LSUHSC-New Orleans. without monitoring or heparin bridging. He had no evidence of infection, no heparin use, no lupus anticoagulant, and no serum cryoglobins. His biopsy showed characteristic intra- vascular thrombosis of small cutaneous vessels. Based on his history, laboratory data, histopathology, and that he was heterozygous for Factor V Leiden mutation, we confirmed the diagnosis of WISN. Alcoholism also contributed to the development of WISN in our patient. Acute alcohol ingestion, as in binge drinking, impairs hepatic metabolism of warfarin and in- creases the effective anticoagulant dose. Patients with Factor V Leiden mutation requiring anticoagulation with warfarin should receive extensive counseling regarding alcohol use and the risk of re-initiating therapy after self-discontinuation without heparin bridging. Consideration should be given to alternative oral anticoagulation (rivaroxaban, dabigatran) for patients with risk factors for WISN.

REFERENCES

1. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000;87(3): 266–72. 2. McKnight JT, Maxwell AJ, Anderson RL. Warfarin necrosis. Arch Fam Med 1992 Sept;1(1):105-8. 3. Ansell J, Hirsch J, et al. The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:204S-233S. 4. Broekmans AW, Teepe RG, van der Meer FJ, et al. Protein C and coumarin-induced skin necrosis. Thromb Res 1986;6:137. 5. Goldberg SL, Orthner CL, et al. Skin necrosis following a prolonged administration of coumarin in a patient with inherited protein C deficiency. Am J of Hematology 1991;38:64-6.

234 J La State Med Soc VOL 165 May/June 2013